Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model.
Peripheral nerve injury resulting in neuropathic pain induces the upregulation of interleukin (IL)-6 and tumor necrosis factor-alpha, which binds to tumor necrosis factor receptor 1 (TNFR1) and induces NF-kappaB and p38 MAPK activation in the spinal cord and dorsal root ganglia (DRG). We here investigated whether TNFR1 regulates IL-6 expression through NF-kappaB or p38 MAPK activations in the spinal cord and DRG in rats with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal treatment with a TNFR1 antisense oligonucleotide (ASO) significantly inhibited CCI-elevated IKKs phosphorylation, IkB-alpha degradation, the nuclear translocation, phosphorylation, and DNA-binding activity of NF-kappaB, p38 MAPK activation, and IL-6 mRNA and protein expression in the spinal cord and DRG. Interestingly, CCI remarkably elevated IKKalpha and p65 phosphorylations in the spinal cord rather than in the DRG. In addition, NF-kappaB decoy, but not p38 MAPK inhibitor, SB203580 reduced CCI-elevated IL-6 expression in the spinal cord and DRG. Therefore, these data suggest that TNFR1 induces IL-6 upregulation and neuropathic pain through NF-kappaB, but not p38 MAPK activation in the spinal cord and DRG and that the NF-kappaB/IL-6 pathways in the DRG may be less dependent on TNFR1 than the spinal cord pathway.
Lee
Kyung-Min
KM
Department of Anatomy, School of Medicine, Kyungpook National University, 2-101, Dongin-Dong, Daegu 700-422, South Korea.
Jeon
Sang-Min
SM
Cho
Hee-Jung
HJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D015850:Interleukin-6 / Q000096:biosynthesis*; D008297:Male; D016328:NF-kappa B / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D047888:Receptors, Tumor Necrosis Factor, Type I; D048051:p38 Mitogen-Activated Protein Kinases